Although delayed (subacute and chronic) brain injury is a common clinical problem after hypoxic-ischemic insults, it has been little studied, and no conventional therapies have proven effective. The goal of this proposal is to establish the neuroprotective effect of combined herbal therapy (CHT) in attenuating delayed injury after global cerebral ischemia and to investigate mechanisms of protection. In China, CHTs have been used for centuries to improve disturbed circulation and encourage healing, and they have been applied successfully to treat brain ischemia for 40 years. Recent studies identified 9 herbs possessing particularly powerful antioxidant, anti-inflammatory, and anti-platelet activities. In our preliminary studies of brief global ischemia, which triggers slowly progressive alterations of neurons, glia and endothelium and the abnormal cerebral accumulation of beta-amyloid precursor protein (beta-APP) and amyloid beta peptide (A-beta), 6-week treatment with a CHT of these 9 herbs attenuated neurodegeneration, endothelial degeneration and infarction, and decreased beta-APP and A-beta accumulation. In the proposed studies, we shall first confirm the effect of CHT at various survival time points (3 days - 8 weeks) on reducing delayed secondary injury resulting from transient normothermic cerebral ischemia. This experiment will specifically explore the efficacy of CHT on the expression of inflammatory mediators, including nitric oxide synthase (iNOS) and cyclo-oxygenase-2 (COX-2), and on the attenuation of BBB disruption and microglial activation. A subgroup of CHT will be tested for its efficacy in reducing A-beta and beta-APP deposition. Next, we shall test whether CHT can protect against the exaggerated chronic injury produced by ischemia complicated by mild hyperthermia. We suspect that this process involves endothelial injury and inflammatory mechanisms and may respond to CHT. Finally, we shall test whether CHT administered prior to an ischemic insult (and continued after ischemia) would also be capable of reducing acute neuropathological alterations. We shall make extensive use of quantitative histopathology, image-analysis, and immunohistochemistry of COX2, iNOS, A-beta, beta-APP and multiple markers of neuronal, glial, and endothelial integrity or injury.